Pharmacology: Anxiolytic, Sedative and Hypnotic Drugs

Anxiolytic, Sedative, and Hypnotic Effects

• Anxiolytic effect: reducing psychomotor reactivity exceeding normal limits to a normal level of attention and responsiveness
• Sedative effect: reducing vigilance and psychomotor reaction ability below normal limits
• Hypnotic effect: inducing sleep

Hypnos Sedative Medications

• Benzodiazepines
• Non-benzodiazepine BZ receptor agonists
• Barbiturates
• Azopyrones (e.g., buspirone, gepiron, ipsapiron) - anxiolytic
• Antihistamines (e.g., hydroxyzine, doxylamine, diphenhydramine, metaprine, promethazine)
• Melatonin, ramelteon
• Others (e.g., aldehydes, propanediol, carbamate derivatives, piperidindiones, quinazolins)

Effects of Hypnos Sedatives

• Dose-dependent and generalized CNS depression
• Drowsiness below sedative dose
• Sedative (anxiolytic) at small doses
• Hypnotic at high doses (narcotic)
• General anesthesia and coma at overdose
• Anticonvulsant and central muscle relaxant effects

Mechanisms of Action of Hypnos Sedatives

• BZ receptors: BZ1 (anxiolytic and sedative), BZ2 (muscle relaxation, CNS depression, and psychomotor changes), BZ3 (located in the SSS and periphery, responsible for tolerance and withdrawal symptoms)
• GABA: agonist (mucimol), antagonist (bicuculin)
• Benzodiazepines: reverse agonists and antagonists (allosteric) on the junction of alpha and gamma subunits of the GABAA receptor
• Barbiturates: allosteric, picrotoxin (blocks the channel directly)
• Ethanol, ivermectin, etomidate, propofol, and gas general anesthetics

Benzodiazepines

• Mechanism of action: activating the binding points (BZ1 and BZ2 receptors) on the GABAA receptor, causing the opening of chloride channels, hyperpolarization, and postsynaptic or presynaptic inhibition
• Interactions with other mediators: affecting the serotonergic system, reducing serotonergic tone, inhibiting the locus coeruleus, suppressing the central cholinergic system, and inhibiting adenosine uptake
• Classification:
  • Long-acting (e.g., diazepam, klonazepam, klorazepat, medazepam, flurazepam, kuazepam)
  • Medium-acting (e.g., oxazepam, alprazolam, lorazepam, temazepam, nitrazepam, flunitrazepam)
  • Short-acting (e.g., midazolam, triazolam)

Properties of Benzodiazepines

• Lipophilic
• Quickly absorbed from the GI canal
• Elimination half-life varies from person to person, influenced by age
• Preference for oxazepam and lorazepam in the elderly and liver dysfunctions
• Metabolized by CYP 3A4 and CYP2C19, excreted in the form of conjugates
• Long-acting benzodiazepines: no long effects when used in a single dose, requiring 5-14 days of treatment for a significant effect
• Short- and medium-acting benzodiazepines: greater potential for physical addiction and risk of amnesia

Uses of Benzodiazepines

• Anxiety disorders (e.g., panic reactions, phobias)
• Sleep disorders
• Induction of general anesthesia and short-term surgical or diagnostic interventions
• Anticonvulsants (e.g., clonazepam, midazolam, nitrazepam, triazolam)
• Striated muscle rigidity and spasm, nocturnal myoclonus, athatosis
• Tetanus, febrile convulsion, status epilepticus, and withdrawal syndrome

Side Effects of Benzodiazepines

• Drowsiness, mental and psychomotor dysfunction
• Impaired motor coordination, ataxia, nystagmus, drunken speech
• Anterograde amnesia, dementia
• Disruption in jobs that require skill
• Headache, dizziness, nausea, vomiting
• Decreased visual acuity, joint pain
• Addiction: physical dependence occurs without significant psychic dependence in use for more than 6 weeks

Azapirones

• Partial agonist at serotonergic receptors of type 5HT1A
• Reduces serotonergic activity in the limbic system
• No hypnotic effect, no tolerance, and non-addictive
• Superiority over benzodiazepines: fewer psychomotor disorders, less sedation and amnesia, no interaction with alcohol, and no tolerance and dependence with benzodiazepines and other sedatives

Barbiturates

• Classification by duration of action:
  • Long-acting (e.g., phenobarbital, sedative and anticonvulsive)
  • Medium-acting (e.g., pentobarbital, allobarbital, amobarbital, hypnotic, butalbital, siklobarbital)
  • Short-acting (e.g., sekobarbital, hexobarbital)
  • Very short-acting (e.g., thiopental, IV anesthetic)
• Pharmacokinetic properties: quickly absorbed through the GI duct, absorbed and used through the rectum, IM absorption is quick, easily passes into milk
• Pharmacodynamic properties: sedative and hypnotic effect, anticonvulsant effect, general anesthesia

Side Effects of Barbiturates

• Drowsiness and residual effect
• Impaired cognitive functions in infants and children
• Dependence and tolerance
• Rebound insomnia
• Allergic reactions, respiratory depression, paradoxical excitation
• Exacerbation of porphyria, local pain, and myalgia

Drug Interactions

• Additive interaction with other anxiolytic and hypnotic drugs
• Alcohol potentiates the effects of barbiturates
• Induction of microsomal enzymes (CYP3A4, CYP2C9) and reduced plasma levels of drugs metabolized by these enzymes

Acute Barbiturate Poisoning

• Symptoms: excessive drowsiness, confusion, slurred speech, decreased respiratory rate, sometimes rapid and superficial breathing
• Treatment: respiratory support, prevention and treatment of shock, maintenance of renal function, forced diuresis, peritoneal dialysis, hemodialysis

Other Hypnosedative Drugs

• Dexmedetomidine: central sympatholytic, sedative, and analgesic effects
• Agomelatine: MT1 and 2 and 5-HT2C receptors

Anxiety Disorders

• Generalized anxiety disorder
• Panic disorder
• Social anxiety disorder
• Post-traumatic stress disorder
• Obsessive-Compulsive disorder

Basic Sleep Disorders

• Insomnia
• Sleep breathing disorders (e.g., obstructive sleep apnea syndrome)
• Excessive sleepiness that is not due to breathing disorder during sleep (e.g., narcolepsy, hypersomnia)
• Circadian rhythm disturbances
• Parasomnias (e.g., making the patient's environment safe, MAO inh, alcohol and caffeine restriction)
• Sleep-related movement disorders (e.g., restless legs syndrome)### Sleep-Related Movement Disorders
• Elimination of iron deficiency, dopamine agonists, benzodiazepine, carbamezapine, and gabapentin can be used to treat sleep-related movement disorders

Insomnia

• Insomnia is characterized by difficulty falling asleep, difficulty maintaining sleep, frequent awakenings, and early awakening
• Its prevalence in the population is between 30-40%, and it accounts for 50-80% of all sleep disorders

Sleep Hygiene

• Getting up at the same time every morning
• Ensuring consistent bedtime and removing daytime sleeps
• Exercising regularly, but avoiding physically strenuous activities until 3-4 hours before bedtime
• Creating a sleep-conducive environment with minimal noise, light, and heat
• Avoiding eating close to bedtime (up to 2 hours before bedtime)
• Avoiding caffeine, alcohol, cola drinks, and tobacco use at least 6 hours before bedtime
• Not forcing oneself to sleep in bed when unable to sleep at night
• Using relaxation techniques such as breathing exercises before bed

Sleep Periods

• A good sleep pill should reduce the REM pattern and duration of REM without changing the total sleep time
• Hypnotic drugs shorten the time it takes to fall asleep and some shorten REM time significantly
• Short-acting hypnotics are suitable for those who have difficulty falling asleep
• Medium-duration hypnotics are suitable for those who have difficulty starting and maintaining sleep
• Hypnotics with a long duration of action are suitable for those who wake up early in the morning and have anxiety during the day

Pharmacological Treatment of Insomnia

• Benzodiazepine Receptor Agonists (estazolam, flurazepam, quazepam, temazepam, triazolam) shorten the time to sleep, prolong total sleep time, reduce wakefulness, and prolong NREM
• Non-benzodiazepine agonists (Zopiclone, Eszopiclone, Zolpidem, Zaleplon, Indiplon) bind to GABA A receptors and have weaker muscle relaxant and anticonvulsant effects
• Antidepressants (trazodone, mirtazapine, amitriptyline) increase deep sleep and do not shorten REM
• Antihistamines (diphenhydramine, hydroxyzine, doxylamine) can be used to treat insomnia
• Melatonin and ramelteon (MT1 and 2 receptor agonist) regulate the sleep-wake cycle and can treat jet lag
• Valerian (Valeriana officinalis) makes it easier to fall asleep and regulates GABAa receptors

Learn about anxiolytic, sedative and hypnotic effects of drugs, including their definitions and effects on psychomotor reactivity and vigilance.